xenotransplantation – Inside Pediatrics

Xenotransplantation Takes Steps Toward Clinical Trials

_{^{Children’s of Alabama cardiothoracic surgeon David Cleveland, MD, MBA, leader of the xenotransplantation program at Children’s of Alabama and the University of Alabama at Birmingham (UAB).}}

News that surgeons at the University of Maryland Medical Center had implanted a genetically modified pig’s heart into a human rocked the medical world earlier this year. But it didn’t surprise Children’s of Alabama cardiothoracic surgeon David Cleveland, MD, MBA, who is leading a similar xenotransplantation program at Children’s and the University of Alabama at Birmingham (UAB).

The program focuses on developing genetically modified solid organs from pig models for transplantation. To date, Cleveland’s team has successfully transplanted a genetically modified pig kidney into a brain-dead patient. The kidney produced urine.

Three years ago, Cleveland presented preliminary results from a study showing little reactivity in an infant’s blood to cells from a triple-knockout (TKO) pig. The pig had been genetically modified to delete the three major antigens that react with natural human anti-pig antibodies. Even those human cells that did react demonstrated a very mild reaction.

Back then, Cleveland said the next step was a transplant in a non-human primate, something required before the FDA would approve human trials.

Now he’s done it. So far, Cleveland and his team have implanted four infant baboons with the genetically modified pig hearts, with one of the animals living as long as eight months. In humans, the goal isn’t to have the heart last a lifetime but, rather, just long enough for a human heart to become available for transplant.

“I think we have to consistently demonstrate a four-to-six-month survival in non-human primates before the FDA approves a clinical trial,” Cleveland said. The team plans to implant more animals with the hearts this fall and is working on several grants to continue funding the study. Cleveland hopes to be able to submit the design for a clinical trial to the FDA sometime in 2024. In the meantime, he and his team published the results of the first baboon study in The Annals of Thoracic Surgery.

It’s quite possible, however, that the first transplant might occur outside a clinical trial with a humanitarian device exemption from the FDA. The authorization allows a device—in this case, the pig heart—to be used without showing effectiveness in formal clinical trials. That’s how the patient at the University of Maryland Medical Center was able to receive his heart.

“But our goal, ultimately, is to participate in an NIH-funded clinical trial,” Cleveland said, adding that those trials are conducted in more patients with strict safety monitoring and comprehensive data collection.

September 2, 2022 by childrensal

Cardiology, Uncategorized

Understanding Xenotransplantation’s Potential to Save Babies

The issue is simple: there are simply not enough hearts for all the children who need them. So 17% of all children who need a heart transplant die while waiting; this translates to 20% to 25% of infants.[1]

The University of Alabama at Birmingham (UAB) and Children’s of Alabama aim to change those dismal statistics with one of the most revolutionary approaches since the first heart was transplanted from one human to another in 1967 – xenotransplantation.

Thanks to a $19.5 million grant from biotechnology magnate United Therapeutics Corporation, UAB and Children’s have launched one of the top programs in the world dedicated to developing genetically modified solid organs from pig models for transplantation.

The idea isn’t new. Pig tissue has been used to replace heart valves for years, said cardiothoracic surgeon David Cleveland, M.D., MBA, who leads the program at Children’s. The greatest challenge with solid organs, he said, is overcoming immunological and physiological barriers.

If they can do that, “We believe that there’s huge potential to improve the lives of children,” he said.

Supporting Evidence

Earlier this year, Cleveland presented preliminary results from a study showing little reactivity in an infant’s blood to cells from a triple-knockout (TKO) pig. The pig had been genetically modified to delete the three major antigens that react with natural human anti-pig antibodies. Even those human cells that did react demonstrated a very mild reaction.

“We found that very promising,” Cleveland said.

Another area of interest is producing immune tolerance by transplanting porcine thymus tissue to “re-educate” the immune system to accept the pig heart, said cardiac intensivist Leslie Rhodes, M.D. The idea comes from the fact that children can develop an immune system via a human thymus transplant. “We wonder if we could we train their immune system to be tolerant to the pig thymus transplant,” she said.

Infants are the ideal starting place, Cleveland said, not only because they have the highest wait list mortality of any other demographic waiting for a solid organ transplant, but because their immune systems are still naïve. Indeed, they do not develop antibodies to pig glycans during at least the first three months of life, Cleveland and his team wrote in a recent journal article, providing a “window of opportunity” for the transplant.[2]

The next step is a transplant in a non-human primate. “The FDA won’t even consider it until we can prove consistent survival in a non-human primate,” Rhodes said. They hope to perform their first transplant later this year.

Societal Concerns Addressed

The team is also aware of the societal issues around xenotransplantation. To address that, they surveyed the families of patients on the transplant list and the nurses and physicians who will care for these children.

”I was surprised by how positive they were,” Cleveland said. “I thought there would be more pushback than there was.” Still, he said, “I think there has to be major education,” once xenotransplantation becomes a reality. “The idea of replacing a heart with a pig heart will take some people a little time to get over.”

He’s confident it will happen, though. “UAB is going to be one of the centers in the world with the potential to make this happen,” he said. “We have children living in our ICU because there’s not enough cardiac function; they are having their birthdays here. It totally changes entire families to have a child in the hospital forever. There has to be another way.“

[1] Dipchand AI. Current state of pediatric cardiac transplantation. Ann Cardiothorac Surg. 2018;7(1):31–55. doi:10.21037/acs.2018.01.07

[2] Cleveland D, Adam Banks C, Hara H, Carlo WF, Mauchley DC, Cooper DKC. The Case for Cardiac Xenotransplantation in Neonates: Is Now the Time to Reconsider Xenotransplantation for Hypoplastic Left Heart Syndrome? Pediatr Cardiol. 2019;40(2):437-444.

Cutting-Edge Research

Learn more about various research areas at the University of Alabama at Birmingham.

August 20, 2019 by childrensal